Guidelines for diagnosis and treatment in neurology - Lyme neuroborreliosis.

Lyme borreliosis is the most common tick-borne infectious disease in Europe. A neurological manifestation occurs in 3–15% of infections and can manifest as polyradiculitis, meningitis and (rarely) encephalomyelitis. This S3 guideline is directed at physicians in private practices and clinics who treat Lyme neuroborreliosis in children and adults. Twenty AWMF member societies, the Robert Koch Institute, the German Borreliosis Society and three patient organisations participated in its development. A systematic review and assessment of the literature was conducted by the German Cochrane Centre, Freiburg (Cochrane Germany). The main objectives of this guideline are to define the disease and to give recommendations for the confirmation of a clinically suspected diagnosis by laboratory testing, antibiotic therapy, differential diagnostic testing and prevention.


Reasons for selecting the guideline topic
Lyme borreliosis is the most common tick-borne infectious disease in Europe. The Borrelia enter the skin during the blood sucking process of the hard-bodied tick Ixodes ricinus. There they are either inactivated by the innate (congenital) immune system or a local infection occurs. Disease develops in a small proportion of infected patients. Inflammation of the skin frequently occurs, typically as erythema migrans. As the disease progresses, the Borrelia can disseminate and infect various organs such as the skin, nervous system, joints and heart. The nervous system is involved in 3-15% of all patients with Lyme borreliosis. This usually manifests as meningoradiculitis. The late or chronic form of the disease rarely occurs but can lead to encephalomyelitis with an unfavourable prognosis. In very rare cases vasculitis of the arteries to the brain develops with consecutive strokes. If antibiotic treatment is not available or its onset is considerably delayed, serious neurological residuals can persist. Attachment

Guideline objective
This guideline on neuroborreliosis aims to provide: • Recommendations for confirming a clinical diagnosis; clarifying, in particular, which clinical constellation warrants CSF testing • Recommendations for stage-appropriate diagnostic testing: serological detection of IgG Borrelia antibodies using a 2-step ELISA/immunoblot process • Recommendations on determining Borrelia-specific intrathecal antibody synthesis (Borreliaspecific CSF/serum antibody index) • Meaningful use of molecular-diagnostic testing and culture tests • Recommendations on diagnostic certainty (possible, probably, confirmed neuroborreliosis) • Treatment of early-and late-stage neuroborreliosis • Recommendations on monitoring treatment • Recommendations on treating persisting atypical or non-specific symptoms after antibiotic treatment • Prevention of Lyme borreliosis • Recommendations on the follow-up observation of the tick bite • Supplying information to patients (Appendix 6 in Attachment 1) • The guideline does not include information on diseases caused by Borrelia recurrentis (relapsing fever) • Matters pertaining to co-infections linked to tick-borne diseases are not within the scope of this guideline

Patient target group
• Children and adults suffering from neuroborreliosis or suspected of having neuroborreliosis • Patients presenting to a physician for diagnosis and treatment of neuroborreliosis • Patients presenting to a physician with neurological symptoms that indicate neuroborreliosis • Patients whose symptoms persist after antibiotic treatment for neuroborreliosis and who need a differential diagnosis • Patients presenting to a physician with questions about neuroborreliosis • Patients presenting to a physician for a tick bite

Area of care
• In-and out-patient care Target user group/target audience • Information for physicians in private practices and clinics involved in treating neuroborreliosis (see Section 2, Composition of the guideline group: participation of interest groups)

Formulation of key questions
The key questions for the literature survey were formulated at an initial meeting with formal consensus by the consensus group. They were developed with respect to patients, interventions, comparative interventions (comparatives) and patient-relevant endpoints (outcomes) in accordance with the PICO process. The meeting was chaired by an independent moderator from the AWMF in Frankfurt am Main on 11 February 2014.

a) Definition of neuroborreliosis (PICO):
In infectiology, the microbiological detection of pathogens is considered the "gold standard" for defining an infectious disease. Since detecting the pathogen in CSF is not sensitive enough with respect to neuroborreliosis (10-30% sensitivity), diagnostic criteria have been agreed on which  Stanek et al. 2011); this definition differentiates between a "possible", "probable" and "confirmed" case of neuroborreliosis (Section 3.11 of the guideline text).
Discussion on the above procedure: • "Seronegative cases" (controversial) are not taken into account in clinical definitions: Decision: These should be taken into account in the descriptive review and discussed as part of the recommendations under the aspect of their transferability to extended patient groups. To find relevant guidelines, a literature survey was carried out in the electronic database MEDLINE (via Ovid) and in the databases of four guideline networks (National Guideline Clearinghouse (www.guideline.gov), International Guideline Library of the Guidelines International Network (www.g-i-n.net/library/interational-guidelines-library), the National Institute for Health and Care Excellence (NICE, www.nice.org.uk/guidance/published?type=guidelines), and the Association of Scientific Medical Societies (AWMF, www.awmf.org/leitlinien/leitlinien-suche.html). All guidelines published in these databases between 1999 and 2014 and published in German or English have been included (see Appendix for search strategy).
First a literature survey was carried out of the relevant guidelines. A total of 177 guidelines were found, of which only 8 met the inclusion criteria. Six guidelines were issued by scientific societies; the remaining two guidelines were issued by self-help organisations and patient associations.
The "Appraisal of Guidelines for Research and Evaluation II" questionnaire (AGREE II) was used to assess and rate the methodological quality of the guidelines (Brouwers et al. 2010). Assessments were carried out in a total of 6 domains based on predefined assessment criteria (scope of application, participation of interest groups, stringency of guideline development, clarity of design, applicability and editorial independence). These domains were used to calculate an overall percentage rating (%). A guideline receiving an overall rating of <50% is considered to be of low methodological quality (Bouwmeester et al. 2009;Haran et al. 2014).
The domain "Methodological precision of guideline development" is also relevant, as methodological aspects of evidence-based research (systematic literature survey, selection of literature) play a particularly important role in this area. A guideline receiving a rating of <50% in this domain was also considered to be of low methodological quality.
A total of 177 entries were screened in the various databases. After excluding irrelevant entries, 8 guidelines remained. Their full texts were evaluated using the AGREE II tool.
An assessment of the non-excluded guidelines was independently carried out by two experts; their evaluations are presented in Table 1.
Three of these guidelines had an overall rating ≥50%. None of the guidelines included under the aspect "methodological precision" had a value ≥50%. Because the quality of the included guidelines was questionable at best, recommendations from these guidelines were not adopted without further review and our own literature survey was conducted.

Systematic literature survey (Dersch et al. 2015a)
A systematic literature survey was conducted in order to assess the pharmacological processes for treating neuroborreliosis. This was followed by an evaluation and summary of existing literature.
The search strategy and methodology of this systematic review were reviewed and published in advance as part of a peer review process (Dersch et al. 2014). The literature was to be summarised and evaluated separately for adults and children.
Diagnoses had to be made on the basis of internationally agreed case definitions (see above). Studies had to report data on drug therapy for patients with neuroborreliosis and include a control group.

Selecting evidence
A survey of the literature found a total of 5,779 entries after duplicates were removed. Irrelevant entries were eliminated by screening the titles and abstracts of each entry. This left 119 texts that were examined in their entirety. A further 86 entries were excluded on the basis of being irrelevant. Of the remaining 33 studies, 17 studies had only one treatment arm so no data could be extracted for statistical comparisons. A total of 16 studies had two or more treatment arms and thus data could be extracted for a meta-analysis. Of these 16 trials, eight were randomised controlled trials (RCTs). Figure 1 is a flow chart showing the studies that were included (PRISMA statement). The characteristics of the RCTs are shown in Table 2.

Evaluation of the evidence
The quality of the individual RCTs was investigated and evaluated using the risk-of-bias tool from the Cochrane Collaboration (www.handbook.cochrane.org). The quality of the non-randomised studies (cohort studies) was measured using the ACROBAT-NRSI tool of the Cochrane Collaboration (www.riskofbias.info). The entire body of evidence was evaluated using the GRADE methodology (Grading of Recommendations Assessment, Development and Evaluation) (Balshem et al. 2011). The data extraction and risk of bias were carried out by two independent experts. For a meta-analysis of the existing studies, pooled effect estimates were calculated for the treatment effects using a "fixed effects model" based on the Mantel-Haenszel method. There were no studies on the treatment of neuroborreliosis in which antibiotic treatment was compared to a placebo.

Creation of evidence tables
The GRADE methodology was used by two experts to independently evaluate the quality of the evidence with regard to the individual comparisons. The evaluation of the individual comparisons is summarised in evidence tables (Tables 3-5).  Two unblinded studies, concerns regarding the allocation and selective reporting 2. Small groups, the 'optimal information size' was not reached, wide confidence interval 3. The 'optimal information size' was not reached, wide confidence interval   Critical risk of bias (interventions not clearly described, baseline confounding, no blinding), meta-analysis is therefore not justified 2.
Low heterogeneity (various interventions, various treatment durations), relevance for effect estimate unclear 3.
The 'optimal information size' was not reached, wide confidence intervals

Treating neuroborreliosis in children (Dersch et al. 2016a)
The body of evidence on treating neuroborreliosis in childhood was also compiled from clinical studies and evaluated in a systematic review. The methodology is based on the systematic review mentioned above on treating neuroborreliosis in adulthood (Dersch et al. 2014).

Systematic literature survey
Inclusion and exclusion criteria were defined and published in advance (Dersch et al. 2014). The patients in the individual studies had to be <18 years old. The diagnosis had to be transparent in the individual studies. There are no established case definitions for diagnosing neuroborreliosis in childhood. Therefore, the diagnostic criteria of neuroborreliosis in adulthood were used as inclusion criteria for the individual studies in the systematic review (cf. guideline Section 3.11). For a metaanalysis of the existing studies, pooled effect estimates were calculated for the treatment effects using a "fixed effects model" based the Mantel-Haenszel method.
A survey of the literature identified a total of 5,779 entries after duplicates were removed. Irrelevant entries were eliminated by screening the titles and abstracts of each entry. This left 44 texts that were examined in their entirety. A further 38 entries were excluded on the basis of being irrelevant.
A total of six studies met the inclusion criteria including two RCTs, a prospective cohort study and three retrospective cohort studies. Figure 2 is a flow chart showing the included studies (PRISMA statement). The study characteristics of the included studies are shown in Table 6.

Selecting evidence
The selected studies and the results of the evidence analysis are shown in Table 6 (see below) and in Section 5.5 of the guideline text.

Creation of evidence tables
The assessment of the individual comparisons is summarised in evidence tables (  Baseline confounding, selected patients, no blinding, unclear description of interventions, meta-analysis therefore not justified 2.

Heterogeneous interventions, interventions not clearly described
3.
The 'optimal information size' was not reached, wide confidence intervals   Small group size, the 'optimal information size' was not reached 3.

Prognosis of neuroborreliosis (Dersch et al. 2016b)
A systematic review investigated the prevalence and spectrum of residual symptoms following neuroborreliosis with the aim of making evidence-based statements on the prognosis and progression of neuroborreliosis (Dersch et al. 2016b). Residual symptoms refer here to neurological symptoms that were present before therapy as disease symptoms and which remain after therapy.

Systematic literature survey
A literature survey was conducted in three electronic databases (MEDLINE, EMBASE and Central) using a previously published, broad-based search strategy (Dersch et al. 2014). The search strategy was the same as in the literature surveys described above for the treatment of neuroborreliosis, however it also contained studies that did not include a control group (studies with only one treatment arm). The diagnosis had to be made on the basis of internationally established case definitions (cf. Section 3.11. of the guideline).  Figure 3.

Selecting evidence
Data on residual symptoms were extracted from the individual studies as reported by the original authors. The data on the spectrum of residual symptoms were combined into categories to allow a meaningful comparison (e.g. data on "facial nerve palsy" and "aducens nerve palsy" were placed into the category "cranial nerve palsy"). It was also recorded how the diagnosis of neuroborreliosis was made in the individual studies. Thus, the patient cohorts of the individual studies were categorised based on the case definitions of neuroborreliosis.  Figure 3: Included studies on residual symptoms following neuroborreliosis

Prevalence of residual symptoms
The prevalence of residual symptoms across all available studies was compiled in a meta-analysis.
Since the heterogeneity of study populations was assumed to be high, a "random effects model" was used to calculate the meta-analysis for the prevalence of residual symptoms. The meta-analysis showed a prevalence of residual symptoms after treatment of 28% (95% CI 23-34%) across all studies. The prevalence of residual symptoms differed depending on the case definition used. In studies that included patients without a diagnosis confirmed by CSF testing ("possible neuroborreliosis"), residual symptoms were statistically significantly more frequent than in studies that included patients with a neuroborreliosis diagnosis confirmed by CSF testing ("probable" and "confirmed" neuroborreliosis) (31% vs. 24%, p=0.0048).

Spectrum of the residual symptoms
The spectrum of residual symptoms was reported for a total of 687 patients in studies where the diagnosis was confirmed by CSF testing and for 624 patients in studies without confirmation by CSF testing. The results of the review are presented in Section 4.

Formulation of the recommendations and structured consensus building Formal consensus building: process and implementation
An initial draft of the guideline was developed by Prof. S. Rauer following consensus on the key issues and based on the results of the systematic literature survey. The draft was agreed on in the expert group using a modified Delphi procedure and subsequently brought to a vote in the consensus group using the nominal group technique. Four consensus conferences were held that were independently moderated by the AWMF.
The nominal group technique contained the following steps:

Consideration of benefits, side effects, relevant outcomes
The systematic review found that there is no reliable data on placebo-controlled treatment (Dersch et al. 2015a). At the same time, there are analysable studies comparing the efficacy and side effects of different classes of antibiotics (Dersch et al. 2015a). These are described in Section 5 of the guideline. The relevant studies are summarised in Appendixes 3, 4 and 5 of the guideline (Attachment 1). Appendix 8 of the guideline (Attachment 1) presents an evaluation of the evidence of these studies using the GRADE methodology.

Formulation of the recommendations and the grading of evidence and/or recommendations
In infectiology the microbiological detection of pathogens by culture, microscopy or PCR is the diagnostic gold standard. Accepted case definitions are used in the diagnosis of neuroborreliosis (cf. Section 3.11. of the guideline) since there is no reliable gold standard because pathogen detection in cerebrospinal fluid has a very low sensitivity rate (10-30%). Thus, for methodological reasons, controlled studies on diagnostic testing procedures can only be conducted to a very limited degree.
Evidence grading is provided in the background for all treatment recommendations based on the systematic reviews (Dersch et  Evidence grading: studies on therapy interventions Ia Evidence from a meta-analysis of at least three randomised controlled trials (RCTs) Ib Evidence from at least one randomised controlled trial or a meta-analysis of fewer than three RCTs IIa Evidence from at least one methodologically sound controlled study without randomisation IIb Evidence from at least one methodologically sound, quasi-experimental descriptive study III Evidence from a methodologically sound, non-experimental observational study, such as comparative studies, correlational studies and case studies IV Evidence from reports by expert committees or expert opinions and/or the clinical experience of recognised authorities Uniform formulations are used in order to standardise the guideline recommendations. The following grading applies: Strong recommendation: "shall" ↑↑ Recommendation: "should" ↑ Open recommendation: "can be considered" ↔ Recommendation against an intervention: "should not" ↓ Strong recommendations against an intervention: "shall not" ↓↓ The grading of the recommendations was determined within the framework of formal consensus conferences. In addition to the quality of the underlying evidence, the following criteria were explicitly taken into account: • Consistency in the study results, directness of evidence, precision of the effect estimates (see GRADE profile) •

Stating and countering potential conflicts of interest Explanation and review of interests
The potential conflicts of interest were documented in a structured AWMF form by all persons working on the guideline (members of the steering committee, expert group, consensus group). The potential conflicts of interest were assessed by a panel of expert reviewers appointed by the DGN who worked anonymously, pursued the highest degree of objectivity, were committed to confidentiality and had declared their own interests with respect to the DGN. This evaluation is summarised in a table in an appendix to this report (Attachment 3).

Statement by the DGN experts -panels on assessing conflicts of interest:
The fact that the guideline coordinator Prof. Dr. S. Rauer is co-founder and co-owner of ravo Diagnostika GmbH Freiburg was seen from the start as a conflict of interest. The company develops, produces and markets serological tests for determining Borrelia-specific antibodies as part of routine diagnostic testing. For this reason, S. Rauer was generally not entitled to vote as part of the consensus process. The DGN's vote was cast by PD Dr Stephan Kastenbauer, who was appointed deputy coordinator for this task by the DGN.
Prof. A. Krause, member of the steering committee, declared several interests that did not relate to the topic of this guideline. However, there was not sufficient transparency with regard to the interdependencies and ramifications (subsidiaries) of the pharmaceutical companies involved. Thus, an unconscious bias in the decisions, e.g. with regard to antibiotic treatment, cannot be ruled out. Prof. A. Krause did not participate in voting on pharmacological treatment, in particular, antibiotic therapy.
Formal reasons for conflicts of interest: Dr. Walter Berghoff, German Borreliosis Society (DBG), (member of the consensus group): Imprecise information stated on the interest form, for example, no income was declared from topic-related expert services provided to courts etc.
Ute Fischer, Borreliosis and FSME Association Germany (BFBD), (member of the consensus group): non-fiction author, particularly the Borreliosis Yearbook series. Imprecise information stated on the interest form, for example, no income was declared from publications.
The risk of bias through potential conflicts of interest were countered through: • Interdisciplinary, pluralistic composition of the guideline group with the involvement of representatives with different viewpoints • Systematic survey and assessment of the evidence by the German Cochrane Centre • Structured consensus building moderated by an independent guideline advisor from the AWMF

Overall assessment of those involved
The group of authors comprises 33 members, seven of whom are in the steering group. According to the interest criteria, 28 members (five in the steering group) are free of conflicts of interest or only have minor topic-related conflicts of interest. This means that the criterion of having 50% members without conflicts of interest is met by the group as a whole and by the steering group. Conflicts of interest cannot be ruled out for three members; in the case of two members, as a result of insufficient information given, or doubts about the completeness of the declaration form; in the case of an author (member of the steering group), non-participation in the voting on antibiotic treatment is deemed appropriate. There are potentially serious conflicts of interest for two members (both in the steering group, including the lead coordinator). Their possible influence is neutralised 1) through twice as many unencumbered members of the steering group, 2) through a second coordinator, 3) through abstention of voting by the lead coordinator, 4) through an overwhelming majority of members of the author group without conflicts of interest.
In summary, the measures to limit possible conflicts of interest are deemed sufficient to ensure the independence of the decision-making used to prepare this guideline according to the criteria of the DGN and AMWF. The group of authors is well-balanced.

Concept for distribution and implementation
Websites of the AWMF and DGN; translation into English and publication in an international journal with focus on evidence-based medicine; presentation of the guideline at congresses.

Applying the guideline recommendations
Since the recommended diagnostic testing and treatment can be performed both on an in-patient and out-patient basis depending on the nature of the symptoms, and the recommended antibiotics can be administered both orally and intravenously, few organisational problems are likely to arise when implementing the recommendations. As the recommended antibiotics are available in generic form, cost bearers should have no issues in applying the guideline.

Validity period and updating procedures
The guideline is valid for 3 years from the publication date (12 April 2018); 6 months before the expiry date, a literature survey shall be conducted with respect to existing systematic reviews and systematically evaluated for the subsequent period. The correspondingly updated manuscript will be discussed as part of a new consensus procedure, and the key recommendations will be reviewed with respect to their relevance to the current situation. Prof. Dr. S. Rauer and Dr. R. Dersch are responsible for updating the guideline in consultation with the DGN Guideline Commission.